Reproductive immunology has been a recognised field for over 40 years, with hundreds of doctors practising across multiple countries. Research in this area is published in leading journals such as the American Journal of Reproductive Immunology and shared through organisations like the European and American Societies for Reproductive Immunology.
Despite its long-standing presence and extensive research, this remains a controversial area of medicine, marked by differing opinions and conflicting findings.
The Immune System
The immune system is the body’s defence force, always on alert for invaders such as germs and viruses. It’s made up of different components, each with a specific job—like members of a well-coordinated team.
- B cells are like intelligence agents. They make antibodies—proteins that tag germs so other immune cells can destroy them.
- T cells are like soldiers. Some, called helper T cells, coordinate the immune response. Others, like killer T cells, attack infected or abnormal cells directly.
- Natural killer (NK) cells are the rapid response team. They can detect and destroy abnormal cells, including virus-infected cells and cancer cells, without needing prior exposure.
Then there are cytokines, which act like messengers. These tiny proteins help immune cells talk to each other. Some cytokines encourage cells to multiply and attack; others help to calm inflammation and regulate the response.
Together, these cells and signals form a powerful defence network that keeps us healthy. But if this system becomes unbalanced, it can cause problems—including fertility issues.
Key Players in Reproductive Immunology
T Cells
T cells play a key role in defending the body, but they also help maintain balance. Two subtypes are especially important in fertility:
- Regulatory T cells (Tregs) help prevent the immune system from overreacting and attacking the body’s own tissues. This is especially important during pregnancy, when the mother’s immune system must accept the embryo—which is partly foreign due to the father’s genes. Tregs help create tolerance to the embryo and reduce inflammation, increasing the chances of a healthy pregnancy.
- Helper T cells (Th1 and Th2) are like team leaders.
- Th1 cells are more aggressive and good at fighting viruses and bacteria that hide inside cells.
- Th2 cells have a calming effect, promoting antibody production and reducing inflammation.
A balance between Th1 and Th2 cells is crucial. Too much Th1 activity can lead to autoimmune conditions such as multiple sclerosis, rheumatoid arthritis, or Crohn’s disease. In terms of fertility, it may be linked to miscarriage and pregnancy complications. On the other hand, if Th1 is overly suppressed, the body may become vulnerable to infections and even cancer.
Cytokines and Chemokines
Cytokines are small proteins that act like traffic signals, directing immune cells where to go and what to do. They are made by many types of cells, especially immune cells.
- Interleukins help white blood cells communicate.
- Interferons help fight infections.
- Some cytokines promote inflammation, while others calm it down.
When cytokines are well-balanced, the body can fight infections and heal properly. But when this balance is disrupted, it can cause chronic inflammation, autoimmune disease, or problems with fertility and pregnancy.
Natural Killer (NK) Cells
NK cells are powerful defenders. Unlike most immune cells, they don’t need prior exposure to a germ to launch an attack. They kill abnormal cells by triggering cell death through substances like perforin and granzymes. They also produce important cytokines such as interferons and tumour necrosis factor alpha (TNF-α), which help manage inflammation and fight infections.
During pregnancy, a special type of NK cell called uterine NK cells (uNK cells) are found in large numbers in the lining of the uterus. These cells are less aggressive than those in the bloodstream. Instead of killing cells, uNK cells help support early pregnancy by:
- Assisting in embryo implantation
- Remodelling the uterine arteries to ensure enough blood supply to the growing fetus
- Helping to form the placenta
- Regulating local immune responses to tolerate the embryo
However, if these uNK cells behave abnormally—for example, if they are present in very high numbers or are overly active—they may interfere with implantation and increase the risk of miscarriage or other reproductive problems.
Cluster of Differentiation (CD) Markers
CD markers are like name tags on immune cells. Scientists use them to identify what type of immune cell they’re looking at. For example, a natural killer cell that has the CD56 marker is called CD56+.
This can also be broken down further:
- CD56bright cells (high levels of CD56) are typical of uterine NK cells
- CD56dim cells (low levels) are more common in the bloodstream and are more cytotoxic (cell-killing)
Uterine NK Cells
These are the main type of white blood cells found in the uterus during early pregnancy. Unlike their counterparts in the blood, uterine NK cells don’t attack other cells. Instead, they:
- Increase in number during implantation
- Release substances that help build the placenta
- Help remodel blood vessels to nourish the developing embryo
This makes them vital for a successful pregnancy. But when their function or numbers are out of balance, they may contribute to pregnancy loss or failed implantation.
How Do Oestrogen and Progesterone Affect uNK Cells?
In non-pregnant women, uNK cells rise and fall during the menstrual cycle, peaking just before menstruation. During early pregnancy, their numbers increase dramatically. This is partly because they move from the bloodstream into the uterus and become larger and more active.
Both oestrogen and progesterone directly influence how these cells work. They attach to specific receptors in NK cells and trigger gene expression, affecting:
- Blood vessel formation
- Immune regulation
- NK cell recruitment and activity
For example, progesterone boosts the production of interleukin-15 and VEGF—factors that encourage NK cells to grow, migrate to the uterus, and support pregnancy.
While the full effects of oestrogen are still being studied, we know that both hormones are essential in creating the right environment for embryo implantation and maintaining a healthy pregnancy.